1. Field of the Invention
This invention relates to the use of opioid antagonists such as naltrexone, naloxone or nalmephene alone or with either nicotine replacement therapy or with other withdrawal attenuating agents, to increase smoking abstinence rates, to decrease craving for cigarettes, reduce relapse to heavy smoking during detoxification or once smoking abstinence has been achieved, and to reduce weight gain associated with smoking cessation.
2. Description of the Related Art
Tobacco dependence continues to be a major health hazard for millions of Americans, and because smoking may pose a health risk for non-smokers as well, smoking cessation treatments are of great public interest.
Dependence is an adaptive biological state induced by chronic drug exposure which manifests itself in various behavioral and physiological responses when drug exposure ceases. Withdrawal from nicotine following chronic use of tobacco products results in the emergence of an abstinence syndrome which reaches its peak intensity within the first day. Cessation of smoking has been shown to result in a number of signs and symptoms of withdrawal such as increases in irritability, anxiety, restlessness, impatience, somatic complaints, cigarette craving, hunger, insomnia, tremulousness and heart rate as well as difficulty concentrating, all of which are collectively called the tobacco withdrawal syndrome.
In recent years, research efforts have focused on nicotine replacement strategies to treat nicotine withdrawal following smoking cessation. A transdermal nicotine delivery system popularly called the nicotine patch was introduced in 1992. Reported short term success rates for nicotine patch treatment range between 19% after three weeks in a study without concomitant support to 54% with support. In general, nicotine replacement results in quit rates approximately twice that of placebo patches. Detoxification using the nicotine patch may have limited success, in part, because of the long time frame (typically 8 weeks or more) specified for this procedure. Although active patch success rates at six months continue to be better than placebo, they are substantially lower than at the end of active treatment and range from 4% to 43% among active patch users compared with 0% to 30% in placebo patch users depending on the level of psychosocial treatment provided. This suggests the need for new treatments to prevent relapse following detoxification. The significant problem of weight gain observed with smoking cessation, particularly in women, has not been ameliorated by nicotine replacement strategies, and is often cited as a reason for relapse or for not attempting to quit.
The alpha-2 agonist clonidine is used in anxiety disorders and to decrease the abstinence reactions associated with opiate and alcohol withdrawal. Clonidine has also been tried as an alternative treatment for nicotine addiction. Two large placebo controlled trials of oral clonidine indicated that smoking cessation rates were no better that placebo (Davison, et al., Clinical Pharmacol Ther 44:265-7, 1988; Franks, et al., JAMA 262:3011-3, 1989). Since oral clonidine is associated with too many side effects other investigators tried to use transdermal clonidine. A double-blind randomized trial of transdermal clonidine in heavy smokers demonstrated that the success rates of smokers on clonidine was twice that in the placebo treated group (Glassman, et al., JAMA 259:2863-6, 1988) and a recent meta-analytic review confirms the doubling of quit rates with clonidine (Covey, et al., Br J Addiction 86:991-998, 1991). However, other investigators have found that transdermal clonidine attenuated nicotine withdrawal but did not increase smoking cessation (Prochazka, et al., Arch Intern Med 152:2065-9, 1992). A recent study of transdermal clonidine with and without behavior modification failed to demonstrate substantial benefits of clonidine over placebo. Clonidine was superior to placebo only in patients receiving behavior modification only at 6 weeks after smoking cessation (Hilleman, et al., Annals of Pharmacotherapy 27:1025-1028, 1993). Therefore, although clonidine is known to reduce nicotine withdrawal the efficacy of clonidine as a treatment for nicotine addiction remains controversial.
It would be desirable to have alternate treatments for nicotine cessation (detoxification) that are rapid, to prevent relapse during more gradual detoxification and after nicotine withdrawal, and to reduce weight gain typically observed during and after nicotine withdrawal.